Cerebral vascular calcium signaling in diabetic Alzheimer's disease-related dementias
糖尿病阿尔茨海默病相关痴呆的脑血管钙信号传导
基本信息
- 批准号:10117843
- 负责人:
- 金额:$ 32.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-15 至 2024-08-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAgreementAlzheimer&aposs DiseaseAlzheimer&aposs disease related dementiaAnimalsAwardBiologyBloodBlood VesselsBlood flowCalcium SignalingCell HypoxiaCellsCerebrovascular CirculationCerebrumCessation of lifeCognitiveComplexDataDementiaDeteriorationDevelopmentDiabetes MellitusDiabetic mouseDiseaseDissociationFundingFunding OpportunitiesHypoxiaImpaired cognitionIn VitroKnock-outLeadLinkMediatingMediationMemoryMemory LossMemory impairmentMitochondriaMolecularMusNerve DegenerationOrganOxidative StressPathologicPathway interactionsPilot ProjectsProcessProductionReactive Oxygen SpeciesResearchResearch PersonnelRieske iron-sulfur proteinRisk FactorsRoleRyanodine Receptor Calcium Release ChannelSeriesSiteSmooth MuscleSmooth Muscle MyocytesTacrolimus Binding ProteinsTestingUnited States National Institutes of HealthVascular DementiaVascular Smooth MuscleWild Type MouseWorkantioxidant therapybasecerebral arterycerebral hypoperfusioncerebrovascularcomorbiditydiabeticexperimental studyglucose metabolismimprovedin vivoinnovationknockout genenew therapeutic targetnoveloverexpressionprogramsprotein expressionresponsetherapeutic targettherapeutically effectivevascular cognitive impairment and dementiavasoconstriction
项目摘要
Alzheimer's disease (AD) and AD-related dementias (ADRD) are the common incurable
neurodegenerative
even
conditions characterized by progressive cognitive deterioration, memory decline and
death. The major forms of ADRD include vascular contributions to cognitive impairment and dementia
(VCID). In agreement, vascular dementia is the second most common form of dementia and the most
frequent comorbidity with AD. Diabetes
may
production
is a leading factor in the development of VCID; the ole of diabetes
primarily occur due to the abnormal glucose metabolism and i ncreased reactive oxygen species (ROS)
in cerebral vascular smooth muscle cells (CASMCs)
r
. In support, antioxidant therapies have
shown promising results in protecting against diabetes-induced VCID and other dementias.
the
molecular mechanisms that link diabetes to the development of VCID remain to be elucidated, and
current treatments for these diseases are neither always effective nor specific.
The
Based on our preliminary findings with previous work, in this project, we propose a novel central
hypothesis that diabetes increases Rieske iron-sulfur protein (RISP)-mediated mitochondrial ROS,
dissociates FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) to remove its
inhibitory effect on RyR2 channel and induce Ca2+ release, which causes cerebral vasoconstriction and
cerebral blood flow reduction, thereby leading to progressive memory loss, cognitive decline and VCID.
To test this exciting hypothesis, we will conduct a series of mechanistic studies primarily by employing
smooth muscle-specific RISP, RyR2, and FKBP12.6 knockout (KO) and/or overexpression (OE) mice with
other complementary advanced experimental approaches to address the following specific questions
(Specific Aims):
Aim 1: Are the increased RISP-mediated mitochondrial ROS in CASMCs essential for VCID induced by
diabetes?
Aim 2: Is RyR2/FKBP12.6 complex dissociation a key consequence for the increased RISP-mediated
mitochondrial ROS to mediate VCID induced by diabetes?
The objectives of the present proposal are not only to enhance our understanding of the molecular
mechanisms for VCID, ADRD
devastating diseases.
and
AD,
but also help to identify novel therapeutic targets for these common
阿尔茨海默病(AD)和AD相关性痴呆(ADRD)是常见的不治之症,
神经变性
甚至
以进行性认知退化、记忆衰退和
死亡ADRD的主要形式包括血管对认知障碍和痴呆的贡献
(VCID)。血管性痴呆是痴呆症的第二大常见形式,
常与AD合并。糖尿病
可以
生产
是VCID发展的主导因素;糖尿病的OLE
主要是由于葡萄糖代谢异常和活性氧(ROS)增加而发生的
脑血管平滑肌细胞(CASMC)
R
.作为支持,抗氧化剂疗法
在预防糖尿病引起的VCID和其他痴呆症方面显示出有希望的结果。
的
将糖尿病与VCID发展联系起来的分子机制仍有待阐明,
目前对这些疾病的治疗既不总是有效也不总是特异性的。
的
基于我们的初步研究结果与以前的工作,在这个项目中,我们提出了一个新的中央
假设糖尿病增加了Rieske铁硫蛋白(RISP)介导的线粒体ROS,
将FK 506结合蛋白12.6(FKBP12.6)与2型兰尼碱受体(RyR 2)解离以去除其
抑制RyR 2通道并诱导Ca 2+释放,导致脑血管收缩,
脑血流量减少,从而导致进行性记忆丧失、认知能力下降和VCID。
为了验证这一令人兴奋的假设,我们将进行一系列的机制研究,主要是通过使用
平滑肌特异性RISP、RyR 2和FKBP12.6敲除(KO)和/或过表达(OE)小鼠,
解决以下具体问题的其他补充性先进实验方法
(具体目标):
目的1:在CASMCs中增加的RISP介导的线粒体ROS对于VCID是必需的吗?
糖尿病?
目的2:RyR 2/FKBP12.6复合物解离是否是RISP介导的细胞凋亡增加的关键结果?
线粒体ROS介导糖尿病诱导的VCID?
本提案的目的不仅是为了加强我们对分子生物学的理解,
VCID、ADRD机制
毁灭性的疾病
和
AD,
还有助于确定这些常见疾病的新治疗靶点,
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitochondrial Dynamics in Pulmonary Hypertension.
- DOI:10.3390/biomedicines12010053
- 发表时间:2023-12-25
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
The Potential Important Role of Mitochondrial Rieske Iron-Sulfur Protein as a Novel Therapeutic Target for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease.
- DOI:10.3390/biomedicines10050957
- 发表时间:2022-04-21
- 期刊:
- 影响因子:4.7
- 作者:
- 通讯作者:
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YONG-XIAO WANG其他文献
YONG-XIAO WANG的其他文献
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{{ truncateString('YONG-XIAO WANG', 18)}}的其他基金
Novel signaling in chronic hypoxic responses in pulmonary arteries
肺动脉慢性缺氧反应的新信号传导
- 批准号:
9186562 - 财政年份:2014
- 资助金额:
$ 32.6万 - 项目类别:
Novel signaling in chronic hypoxic responses in pulmonary arteries
肺动脉慢性缺氧反应的新信号传导
- 批准号:
8979717 - 财政年份:2014
- 资助金额:
$ 32.6万 - 项目类别:
Novel signaling in chronic hypoxic responses in pulmonary arteries
肺动脉慢性缺氧反应的新信号传导
- 批准号:
8825232 - 财政年份:2014
- 资助金额:
$ 32.6万 - 项目类别:
Signaling Mechanisms for Hypoxic Pulmonary Vasoconstriction
缺氧肺血管收缩的信号机制
- 批准号:
8389620 - 财政年份:2012
- 资助金额:
$ 32.6万 - 项目类别:
Signaling Mechanisms for Hypoxic Pulmonary Vasoconstriction
缺氧肺血管收缩的信号机制
- 批准号:
8598510 - 财政年份:2012
- 资助金额:
$ 32.6万 - 项目类别:
Signaling Mechanisms for Hypoxic Pulmonary Vasoconstriction
缺氧肺血管收缩的信号机制
- 批准号:
8237425 - 财政年份:2012
- 资助金额:
$ 32.6万 - 项目类别:
Signaling Mechanisms for Hypoxic Pulmonary Vasoconstriction
缺氧肺血管收缩的信号机制
- 批准号:
8882527 - 财政年份:2012
- 资助金额:
$ 32.6万 - 项目类别:
Mechanisms for hypoxic Ca2+ release in pulmonary artery myocytes
肺动脉肌细胞缺氧释放Ca2+的机制
- 批准号:
7839422 - 财政年份:2009
- 资助金额:
$ 32.6万 - 项目类别:
Novel Signaling for Ca2+ and Release in Airway Myocytes
气道肌细胞中 Ca2 和释放的新信号传导
- 批准号:
7214671 - 财政年份:2003
- 资助金额:
$ 32.6万 - 项目类别:
Heterogeneity of hypoxic Ca2+ release in pulmonary and *
肺和 * 中缺氧 Ca2 释放的异质性
- 批准号:
7104320 - 财政年份:2003
- 资助金额:
$ 32.6万 - 项目类别:
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